The cGAS-STING pathway is a key component of the innate immune response against viral and bacterial infection. Microbial double stranded DNA (dsDNA) within the host cell cytosol is recognised by the DNA sensor cyclic GMP-AMP synthase (cGAS). Once DNA-bound, cGAS generates a second messenger cyclic dinucleotide (CDN) molecule that binds and activates Stimulator of Interferon Genes (STING). STING can also be activated directly by bacterial CDNs during infection. In resting conditions, STING localises to the endoplasmic reticulum (ER) membrane as pre-formed dimers. Upon binding of CDNs, STING traffics to the Golgi and associates with signalling molecules, including the kinase TBK1. Activated TBK1 phosphorylates and activates the transcription factor IRF3, thus promoting the expression of type I interferons (e.g. IFNa/b) for an antiviral response. STING also induces the expression of numerous proinflammatory cytokines, further substantiating the immune response. Subsequently, STING traffics from the Golgi into endolysosomal regions which facilitates its degradation in a negative feedback manner, preventing sustained inflammation.
While STING is known to move through different organelle compartments, the kinetics and mechanisms controlling post-Golgi trafficking events remain poorly defined. To investigate STING translocation in more detail I have utilised both live-cell and super resolution imaging approaches, including spinning disk and Airyscan confocal systems. These high-level imaging modalities have enabled me to observe the dynamic spatiotemporal movement of STING within cells following its activation and gain insights into how STING trafficking mediates its cellular functions. In recent years it has emerged that dysregulation of STING localisation can promote aberrant STING activation and propagate autoimmune and autoinflammatory diseases. Therefore, there is considerable need to understand how STING trafficking events are controlled.